RESUMO
BACKGROUND: Interleukin-16 (IL-16) is an important inflammatory regulator and has been shown to have a powerful effect on the regulation of the inflammatory response. Cardiac inflammation has been reported to be closely related to doxorubicin- (DOX-) induced cardiac injury. In this study, the role of IL-16 in DOX-induced cardiac injury and the possible mechanisms were examined. METHODS: Cardiac IL-16 levels were first measured in DOX- or saline-treated mice. Additionally, mice were pretreated with the anti-IL-16-neutralizing antibody (nAb) or isotype IgG for 1 day and further administered DOX or saline for 5 days. Then, cardiac injury, cardiac M1 macrophage levels, and cardiomyocyte apoptosis were analyzed. The effects of the anti-IL-16 nAb on macrophage differentiation and cardiomyocyte apoptosis were also investigated in vitro. RESULTS: DOX administration increased IL-16 expression in cardiac macrophages compared with that of saline treatment. The anti-IL-16 nAb significantly decreased serum levels of lactate dehydrogenase (LDH), myocardial-bound creatine kinase (CK-MB), and cardiac troponin T (cTnT) and elevated cardiac function in DOX-induced mice. Treatment with the anti-IL-16 nAb also reduced p65 pathway activation, decreased M1 macrophage-related marker and cytokine expression, and protected against cardiomyocyte apoptosis in DOX-induced mice. In cell studies, the anti-IL-16 nAb also reduced DOX-induced M1 macrophage differentiation and alleviated apoptosis in cardiomyocytes cocultured with macrophages. CONCLUSIONS: The anti-IL-16 nAb protects against DOX-induced cardiac injury by reducing cardiac inflammation, and IL-16 may be a promising target to prevent DOX-related cardiac injury.
Assuntos
Anticorpos Neutralizantes/uso terapêutico , Cardiotoxicidade/prevenção & controle , Doxorrubicina/toxicidade , Interleucina-16/antagonistas & inibidores , Miocardite/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Interleucina-16/fisiologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologiaRESUMO
Adult primary immune thrombocytopenia (ITP) is an autoimmune-mediated haemorrhagic disorder. Interleukin-16 (IL-16) can directly affect cellular or humoural immunity by mediating the cellular cross-talk among T cells, B cells and dendritic cells. Several studies have focused on IL-16 as an immunomodulatory cytokine that takes part in Th1 polarization in autoimmune diseases. In this study, we investigated IL-16 expression in the bone marrow supernatant and plasma of ITP patients and healthy controls. What's more, we detected IL-16 expression in ITP patients with the single-agent 4-day high-dose dexamethasone (HD-DXM) therapy. In patients with active ITP, bone marrow supernatant and plasma IL-16 levels increased (P < 0.05) compared with those of healthy controls. In the meantime, the mRNA expression in BMMCs (pro-IL-16, caspase-3) and PBMCs (pro-IL-16, caspase-3 and T-bet) of ITP patients was increased (P < 0.05) relative to those of healthy controls. In patients who responded to HD-DXM therapy, both plasma IL-16 levels and gene expression in PBMCs (pro-IL-16, caspase-3, and T-bet) were decreased (P < 0.05). In summary, the abnormal level of IL-16 plays important roles in the pathogenesis of ITP. Regulating Th1 polarization associated with IL-16 by HD-DXM therapy may provide a novel insight for immune modulation in ITP.
Assuntos
Dexametasona/farmacologia , Imunossupressores/uso terapêutico , Interleucina-16/biossíntese , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Adulto , Medula Óssea/metabolismo , Estudos de Casos e Controles , Caspase 3/biossíntese , Caspase 3/genética , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunossupressores/administração & dosagem , Interleucina-16/sangue , Interleucina-16/genética , Interleucina-16/fisiologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/metabolismo , RNA Mensageiro/biossíntese , Proteínas com Domínio T/biossíntese , Proteínas com Domínio T/genética , Células Th1/imunologia , Doadores de Tecidos , Adulto JovemRESUMO
Disturbance of T-cell homeostasis could lead to intestinal inflammation. Naive CD4 T cells undergoing spontaneous proliferation, a robust proliferative response that occurs under severe lymphopenic conditions, differentiate into effector cells producing Th1- and/or Th17-type cytokines and induce a chronic inflammation in the intestine that resembles human inflammatory bowel disease. In this study, we investigated the key properties of CD4 T cells necessary to induce experimental colitis. α4ß7 upregulation was primarily induced by mesenteric lymph node (mLN) resident CD11b(+) dendritic cell subsets via transforming growth factor beta (TGFß)/retinoic acid-dependent mechanism. Interestingly, α4ß7 expression was essential but not sufficient to induce inflammation. In addition to gut-homing specificity, expression of gut Ag specificity was also crucial. T-cell acquisition of the specificity was dramatically enhanced by the presence of γδ T cells, a population previously shown to exacerbate T-cell-mediated colitis. Importantly, interleukin (IL)-23-mediated γδ T cell stimulation was necessary to enhance colitogenicity but not gut antigen reactivity of proliferating CD4 T cells. These findings demonstrate that T-cell colitogenicity is achieved through multiple processes, offering a therapeutic rationale by intervening these pathways.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Colite/imunologia , Trato Gastrointestinal/imunologia , Integrinas/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Células Th17/imunologia , Animais , Antineoplásicos/farmacologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Colite/metabolismo , Colite/patologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/fisiologia , Proteínas de Homeodomínio/fisiologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-16/fisiologia , Subunidade p19 da Interleucina-23/fisiologia , Linfonodos/imunologia , Linfonodos/metabolismo , Linfonodos/patologia , Veias Mesentéricas/imunologia , Veias Mesentéricas/metabolismo , Veias Mesentéricas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Células Th17/citologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Tretinoína/farmacologiaRESUMO
Given that CD4+ cells are found in the lungs of patients with fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) we hypothesized that IL-16, a potent chemoattractant for CD4+ cells, may be involved in the pathogenesis of this disease. We found that baseline IL-16 gene expression is greater in fibroblasts isolated from IPF patients compared to non-fibrotic fibroblasts. Furthermore, IL-16 gene expression increased in IPF fibroblasts following stimulation with either of the pro-fibrotic growth factors TGFb1 or PDGF. In contrast, PDGF had no effect on IL-16 gene expression in non-fibrotic lung fibroblasts, whereas TGFb1 down-regulated IL-16 gene expression in non-fibrotic fibroblasts. To gain a better understanding of an association of IL-16 with fibrosis, we used the bleomycin-induced mouse model of fibrosis to examine IL-16 gene expression. Our current study demonstrates that IL-16, and its activator caspase 3, are highly expressed at the mRNA level in the lungs of mice prior to the deposition of collagen following intratracheal bleomycin administration. We then sought to determine the role of IL-16 in the generation of fibrosis in the mouse by using IL-16KO mice. There were no differences observed between IL-16WT and IL-16KO mice (cellular infiltrate, collagen deposition, total lung collagen generation and cytokine expression) following bleomycin instillation. These results indicate that IL-16 is prominently expressed in both murine and human fibrosis however as complete loss of this cytokine did not modulate pulmonary fibrosis, IL-16 is a candidate biomarker for IPF.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Bleomicina/farmacologia , Fibrose , Interleucina-16/fisiologia , Pulmão/patologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Colágeno/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose/metabolismo , Citometria de Fluxo/métodos , Interleucina-16/metabolismo , Camundongos , Camundongos Knockout , Modelos BiológicosRESUMO
Primary effusion lymphoma (PEL) is a herpesvirus-8-associated lymphoproliferative disease characterized by migration of tumor cells to serous body cavities. PEL cells originate from postgerminal center B cells and share a remarkable alteration in B cell transcription factor expression and/or activation with classical Hodgkin's disease cells. Comparative analysis of gene expression by cDNA microarray of BCBL-1 cells (PEL), L-428 (classical Hodgkin's disease), and BJAB cells revealed a subset of genes that were differentially expressed in BCBL-1 cells. Among these, four genes involved in cell migration and chemotaxis were strongly up-regulated in PEL cells: leukotriene A4 (LTA4) hydrolase (LTA4H), IL-16, thrombospondin-1 (TSP-1), and selectin-P ligand (PSGL-1). Up-regulation of LTA4H was investigated at the transcriptional level. Full-length LTA4H promoter exhibited 50% higher activity in BCBL-1 cells than in BJAB or L-428 cells. Deletion analysis of the LTA4H promoter revealed a positive cis-regulatory element active only in BCBL-1 cells in the promoter proximal region located between -76 and -40 bp. Formation of a specific DNA-protein complex in this region was confirmed by EMSA. Coculture of ionophore-stimulated primary neutrophils with BCBL-1 cells leads to an increased production of LTB4 compared with coculture with BJAB and L-428 cells as measured by enzyme immunoassay, demonstrating the functional significance of LTA4H up-regulation.
Assuntos
Epóxido Hidrolases/biossíntese , Epóxido Hidrolases/genética , Leucotrieno B4/biossíntese , Linfoma de Células B/enzimologia , Linfoma de Células B/genética , Regulação para Cima , Linhagem Celular Tumoral , Ativação Enzimática/genética , Epóxido Hidrolases/isolamento & purificação , Epóxido Hidrolases/fisiologia , Perfilação da Expressão Gênica , Doença de Hodgkin/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Interleucina-16/fisiologia , Linfoma de Células B/metabolismo , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiologia , Regiões Promotoras Genéticas , RNA Mensageiro/biossíntese , Trombospondina 1/biossíntese , Trombospondina 1/genética , Trombospondina 1/fisiologia , Transcrição Gênica , Regulação para Cima/genéticaRESUMO
Interleukin-16 (IL-16) induces the chemotaxis and activation of mast cells (MCs) and other cell types. While it has been concluded that CD4 is the primary IL-16 receptor on T cells, at least one other IL-16 receptor exists. We now show that the IL-16-responsive human MC line HMC-1 lacks CD4, and that the IL-16-mediated chemotactic and Ca2+ mobilization responses of this cell can be blocked by anti-CD9 monoclonal antibodies (mAbs) but not by mAbs directed against CD4 or other tetraspanins. Anti-CD9 mAbs also inhibited the IL-16-mediated activation of nontransformed human cord blood-derived MCs and mouse bone marrow-derived MCs by 50% to 60%. The chemotactic response of HMC-1 cells to IL-16, as well as the binding of the cytokine to the cell's plasma membrane, was inhibited by CD9-specific antisense oligonucleotides. CD9 is therefore essential for the IL-16-mediated chemotaxis and activation of the HMC-1 cell line. In support of this conclusion, IL-16 bound to CD9-expressing CHO cell transfectants. The ability of wortmannin and xestopongin C to inhibit the IL-16-mediated chemotactic response of these cells suggests that the cytokine activates a phosphatidylinositol 3-kinase (PI3K)/inositol trisphosphate-dependent signaling pathway in MCs. This is the first report of a tetraspanin that plays a prominent role in a cytokine-mediated chemotactic response of human MCs.
Assuntos
Antígenos CD/fisiologia , Interleucina-16/fisiologia , Mastócitos/fisiologia , Glicoproteínas de Membrana/fisiologia , Animais , Antígenos CD/metabolismo , Células da Medula Óssea , Sinalização do Cálcio , Células Cultivadas , Quimiotaxia , Sangue Fetal , Humanos , Interleucina-16/metabolismo , Mastócitos/citologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Tetraspanina 29RESUMO
Whipple's disease (WD) is a rare systemic disease caused by Tropheryma whipplei. We showed that T. whipplei was eliminated by human monocytes but replicated in monocyte-derived macrophages (Mphi) by inducing an original activation program. Two different host molecules were found to be key elements for this specific pattern. Thioredoxin, through its overexpression in infected monocytes, was involved in bacterial killing because adding thioredoxin to infected Mphi inhibited bacterial replication. IL-16, which was up-regulated in Mphi, enabled T. whipplei to replicate in monocytes and increased bacterial replication in Mphi. In addition, anti-IL-16 Abs abolished T. whipplei replication in Mphi. IL-16 down-modulated the expression of thioredoxin and up-regulated that of IL-16 and proapoptotic genes. In patients with WD, T. whipplei replication was higher than in healthy subjects and was related to high levels of circulating IL-16. Both events were corrected in patients who successfully responded to antibiotics treatment. This role of IL-16 was not reported previously and gives an insight into the understanding of WD pathophysiology.
Assuntos
Actinomycetales/citologia , Actinomycetales/crescimento & desenvolvimento , Divisão Celular/fisiologia , Interleucina-16/fisiologia , Doença de Whipple/microbiologia , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Humanos , Macrófagos/microbiologia , Masculino , Pessoa de Meia-Idade , Monócitos/microbiologia , Tiorredoxinas/metabolismo , Transcrição Gênica/fisiologia , Doença de Whipple/metabolismoRESUMO
Prior DNA microarray studies suggested that IL-16 mRNA levels decrease following T cell activation, a property unique among cytokines. We examined pro-IL-16 mRNA and protein expression in resting and anti-CD3 mAb-activated primary murine CD4(+) T cells. Consistent with the microarray reports, pro-IL-16 mRNA levels fell within 4 h of activation, and this response is inhibited by cyclosporin A. Total cellular pro-IL-16 protein also fell, reaching a nadir at 48 h. Pro-IL-16 comprises a C-terminal cytokine domain and an N-terminal prodomain that are cleaved by caspase-3. Pro-IL-16 expressed in transfected tumor cells was previously shown to translocate to the nucleus and to promote G(0)/G(1) arrest by stabilizing the cyclin-dependent kinase inhibitor p27(Kip1). In the present study, we observed increased S-phase kinase-associated protein 2 mRNA expression in IL-16 null mice, but basal expression and activation-dependent regulation of p27(Kip1) were no different from wild-type mice. Stimulation with anti-CD3 mAb induced transiently greater thymidine incorporation in IL-16-deficient CD4(+) T cells than wild-type controls, but there was no difference in cell survival or in the CFSE dilution profiles. Analysis of CD4(+) T cell proliferation in vivo using BrdU labeling similarly failed to identify a hyperproliferative phenotype in T cells lacking IL-16. These data demonstrate that pro-IL-16 mRNA and protein expression are dynamically regulated during CD4(+) T cell activation by a calcineurin-dependent mechanism, and that pro-IL-16 might influence T cell cycle regulation, although not in a dominant manner.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Interleucina-16/metabolismo , Ativação Linfocitária/imunologia , Precursores de Proteínas/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Calcineurina/fisiologia , Ciclo Celular/genética , Ciclo Celular/imunologia , Proliferação de Células , Feminino , Humanos , Interleucina-16/biossíntese , Interleucina-16/deficiência , Interleucina-16/fisiologia , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Precursores de Proteínas/biossíntese , Precursores de Proteínas/deficiência , Precursores de Proteínas/fisiologia , RNA Mensageiro/biossíntese , RNA Mensageiro/metabolismo , Fase de Repouso do Ciclo Celular/genética , Fase de Repouso do Ciclo Celular/imunologia , TransfecçãoRESUMO
Interleukin-16 (IL-16) was the first described T lymphocyte chemoattractant. It has since been shown that IL-16 also functions as a primer of T cell proliferation, a modulator of inflammatory and immune responses, a stimulus of B cell differentiation and an inhibitor of Human immunodeficiency virus (HIV) replication. Its precursor, Prointerleukin-16 (pro-IL-16), is expressed in both the nucleus and cytoplasm of T cells. Cytoplasmic pro-IL-16 serves as the precursor for mature IL-16 while nuclear pro-IL-16 is associated with G0/G1 cell cycle arrest. Herein, we review the ability of IL-16 to act as both primer and modulator of T lymphocyte growth. The impact of IL-16 on T cell apoptosis is also discussed. Finally, we describe the role of pro-IL-16 as a T lymphocyte cell cycle growth suppressor.
Assuntos
Interleucina-16/fisiologia , Linfócitos T/metabolismo , Animais , Apoptose , Núcleo Celular/metabolismo , Proliferação de Células , Citoplasma/metabolismo , HIV/metabolismo , Humanos , Camundongos , Modelos BiológicosRESUMO
The therapeutic potential of interleukin (IL)-16 and derived peptides in allergic asthma is considered, focusing on key interactions with CD4 and associated chemokine receptors. IL-16 is a pleiotropic cytokine that has multiple effector functions with putative roles in varied T cell-mediated inflammatory diseases, such as asthma, inflammatory bowel disease and atopic dermatitis. Both in vitro and in vivo, IL-16 downregulates antigen-driven T cell activation, T helper 2 cytokine production and allergic airway inflammation. Peptides derived from the C-terminal bioactive portion of IL-16 offer advantages related to their retained immunomodulatory properties and absence of signalling in and chemoattraction to T cells.
Assuntos
Asma/tratamento farmacológico , Interleucina-16/fisiologia , Pneumopatias/tratamento farmacológico , Peptídeos/química , Animais , Antígenos CD4/biossíntese , Fatores Quimiotáticos/farmacologia , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Inflamação/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Interleucina-16/metabolismo , Camundongos , Modelos Biológicos , Linfócitos T/metabolismo , Células Th2/imunologiaRESUMO
The precursor for IL-16 (pro-IL-16) is a nuclear and cytoplasmic PDZ domain-containing protein. In this study we have found that pro-IL-16 is absent or mutated in four T lymphoblastic leukemia cell lines examined. Ectopic expression of pro-IL-16 in pro-IL-16-negative Jurkat cells blocks cell cycle progression from G(0)/G(1) to S phase associated with elevated levels of the cyclin-dependent kinase inhibitor p27(KIP1). Pro-IL-16 decreases p27(KIP1) degradation by reducing transcription and subsequent expression of Skp2, a key component of the SCF(Skp2) ubiquitin E3 ligase complex. Taken together, these findings identify pro-IL-16 as a novel regulator of Skp2 expression and p27(KIP1) levels and implicate a role for pro-IL-16 in T cell proliferation.
Assuntos
Proteínas de Ciclo Celular/fisiologia , Fase G1/imunologia , Interleucina-16/fisiologia , Proteínas Nucleares/fisiologia , Precursores de Proteínas/fisiologia , Fase de Repouso do Ciclo Celular/imunologia , Proteínas Quinases Associadas a Fase S/antagonistas & inibidores , Proteínas Quinases Associadas a Fase S/genética , Linfócitos T/imunologia , Proteínas Supressoras de Tumor/fisiologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Morte Celular/genética , Morte Celular/imunologia , Divisão Celular/genética , Divisão Celular/imunologia , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p27 , Citoplasma/imunologia , Citoplasma/metabolismo , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Fase G1/genética , Humanos , Interleucina-16/biossíntese , Interleucina-16/deficiência , Interleucina-16/genética , Leucemia de Células T/imunologia , Leucemia de Células T/metabolismo , Mutação , Proteínas Nucleares/biossíntese , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Precursores de Proteínas/biossíntese , Precursores de Proteínas/deficiência , Precursores de Proteínas/genética , Fase de Repouso do Ciclo Celular/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo , Transcrição Gênica/imunologia , Transfecção , Proteínas Supressoras de Tumor/antagonistas & inibidores , Complexos Ubiquitina-Proteína Ligase/antagonistas & inibidores , Complexos Ubiquitina-Proteína Ligase/metabolismoRESUMO
We postulated that a novel free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone; EDA), would attenuate inflammatory cytokine and chemokine expression in the liver after lipopolysaccharide (LPS) challenge through its antioxidant effect. Rats were administered EDA (0.3, 1.5, 3.0, 6.0, and 12.0 mg/kg) or the same volume of saline intravenously just after LPS (10 mg/kg) injection and then was continued intermittently every 2 h (five administrations in total). Survival was assessed for the next 24 h. In separate experiments, rats were sacrificed at 60 min, 90 min, 6 h, and 9 h after LPS injection. Serum and liver sections were collected for further analysis. Survival was improved by EDA in a dose-dependent manner up to 3 mg/kg, and maximum effects were observed at a dose of 3 mg/kg. After LPS injection, alanine aminotransferase levels increased significantly to about 1,250 IU/l in the vehicle-treated group, whereas values were blunted by about 80% by EDA. Furthermore, increases in 4-hydroxynonenal-modified proteins were also blunted in the liver by EDA. Moreover, mRNA expressions of macrophage infiltrating protein-2, monocyte chemoattractant protein (MCP)-1 and MCP-5 were attenuated by EDA. As a result, increases in the number of infiltrating inflammatory cells and mRNA expression of inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 were significantly blunted in the liver by EDA. This reduction was accompanied by a significant reduction of their serum levels. In conclusion, EDA prevented liver injury by both inhibition of recruitments of inflammatory cells and expression of inflammatory cytokine levels in the liver.
Assuntos
Antipirina/uso terapêutico , Quimiocinas CXC , Endotoxinas/toxicidade , Sequestradores de Radicais Livres/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular , Síndrome do Desconforto Respiratório/prevenção & controle , Alanina Transaminase/metabolismo , Animais , Antipirina/análogos & derivados , Quimiocina CCL4 , Quimiocinas/genética , Quimiocinas/metabolismo , Quimiocinas CC , Modelos Animais de Doenças , Edaravone , Endotoxemia/patologia , Endotoxemia/prevenção & controle , Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Interferon gama/biossíntese , Interferon gama/genética , Interleucina-10/biossíntese , Interleucina-10/genética , Interleucina-16/fisiologia , Interleucina-6/sangue , Leucócitos/fisiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Proteínas Inflamatórias de Macrófagos/biossíntese , Proteínas Inflamatórias de Macrófagos/genética , Masculino , Monocinas/biossíntese , Monocinas/genética , Neutrófilos/metabolismo , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/mortalidade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: IL-16 is an important T-cell chemotactic cytokine in asthmatic airways; its release from allergen-stimulated bronchial mucosa in mild asthma has been shown to be dependent on CD28/B7 costimulation. OBJECTIVE: We have extended our previous studies to investigate the role of IL-16 and CD28/B7 costimulation in T-lymphocyte chemotactic activity (TLCA) released from the bronchial mucosa in more severe asthma. METHODS: TLCA was determined in the supernatants of induced sputum and allergen-stimulated bronchial mucosal explants from healthy volunteers and volunteers with mild and moderately severe asthma by means of a Boyden chamber technique. The contribution of IL-16 to the activity was evaluated through use of a neutralizing monoclonal antibody; the contribution of CD28/B7 costimulation to allergen-induced release of TLCA was determined through use of CTLA4-Ig fusion protein and neutralizing monoclonal antibodies to CD80 (B7.1) and CD86 (B7.2). RESULTS: Induced sputum and unstimulated explants from asthmatic subjects generated significant spontaneous TLCA (P <.05). Both mild and moderate asthmatic explants showed significantly elevated Dermatophagoides pteronyssinus -induced release of TLCA, but only in mild asthma could sputum and allergen-stimulated explant TLCA be inhibited by anti-IL-16 (median inhibition, 39% and 59%; P <.05). In addition, allergen released significant quantities of IL-16 from mild asthmatic explants (P <.05) but not from moderate asthmatic explants. Antibodies to the CD28 counter-ligands CD80 and CD86 inhibited allergen-induced release of TLCA in mild asthmatic explants by 94% (P <.05) and 62%, but TLCA release from moderate asthmatic explants was unaffected by CTLA4-Ig. CONCLUSION: These results show that TLCA release in moderate asthmatic airways, in contrast to mild asthmatic airways, is not dependent on CD28/B7 costimulation and does not involve IL-16.
Assuntos
Asma/imunologia , Antígeno B7-1/fisiologia , Brônquios/imunologia , Antígenos CD28/fisiologia , Quimiotaxia de Leucócito/imunologia , Imunoconjugados , Interleucina-16/fisiologia , Linfócitos T/imunologia , Abatacepte , Adulto , Antígenos CD/fisiologia , Antígenos de Diferenciação/fisiologia , Antígeno B7-2 , Antígeno CTLA-4 , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/fisiologia , Pessoa de Meia-Idade , Escarro/imunologiaRESUMO
AIDS patients often contain HIV-1-infected mast cells (MCs)/basophils in their peripheral blood, and in vivo-differentiated MCs/basophils have been isolated from the blood of asthma patients that are HIV-1 susceptible ex vivo due to their surface expression of CD4 and varied chemokine receptors. Because IL-16 is a ligand for CD4 and/or an undefined CD4-associated protein, the ability of this multifunctional cytokine to regulate the development of human MCs/basophils from nongranulated progenitors residing in cord or peripheral blood was evaluated. After 3 wk of culture in the presence of c-kit ligand, IL-16 induced the progenitors residing in the blood of normal individuals to increase their expression of chymase and tryptase about 20-fold. As assessed immunohistochemically, >80% of these tryptase(+) and/or chymase(+) cells expressed CD4. The resulting cells responded to IL-16 in an in vitro chemotaxis assay, and this biologic response could be blocked by anti-IL-16 and anti-CD4 Abs as well as by a competitive peptide inhibitor corresponding to a sequence in the C-terminal domain of IL-16. The additional finding that IL-16 induces calcium mobilization in the HMC-1 cell line indicates that IL-16 acts directly on MCs and their committed progenitors. IL-16-treated MCs/basophils also are less susceptible to infection by an M/R5-tropic strain of HIV-1. Thus, IL-16 regulates MCs/basophils at a number of levels, including their vulnerability to retroviral infection.
Assuntos
Basófilos/imunologia , Basófilos/virologia , HIV-1/imunologia , Interleucina-16/fisiologia , Mastócitos/imunologia , Mastócitos/virologia , Antivirais/fisiologia , Basófilos/citologia , Cálcio/metabolismo , Sinalização do Cálcio/imunologia , Diferenciação Celular/imunologia , Células Cultivadas , Quimiotaxia de Leucócito/imunologia , Sangue Fetal/citologia , Sangue Fetal/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/crescimento & desenvolvimento , Humanos , Imunidade Inata/imunologia , Interleucina-16/sangue , Mastócitos/citologia , Células-Tronco/citologia , Células-Tronco/imunologia , Células Tumorais Cultivadas , Replicação Viral/imunologiaRESUMO
BACKGROUND: CD4+ T cells constitute a major source of cytokines in allergic diseases such as allergic rhinitis. Interleukin (IL)-16 selectively recruits CD4+ cells. METHODS: We evaluated the effect of natural allergen exposure during a grass-pollen season on IL-16 expression and number of CD4+ cells in nasal mucosa. Patients with allergic rhinitis (n=16) were treated with either a nasal glucocorticoid beclomethasone (BDP; 400 microg/day) or placebo, and gave nasal biopsies prior to and during the grass-pollen season. The evaluated markers in allergic rhinitis patients were also compared to those in healthy control subjects (n=5). RESULTS: Prior to the pollen season, the expression of IL-16, but not the number of CD4+ cells, was significantly higher in patients with allergic rhinitis than in healthy control subjects. The grass-pollen season further increased IL-16 expression and also increased the number of CD4+ cells in placebo-treated, but not in BDP-treated, allergic rhinitis patients. The pollen-season-induced change in IL-16 expression and in CD4+ cells was significantly more pronounced in placebo- than in BDP-treated patients. There was a significant correlation between the change in IL-16 expression and the number of CD4+ cells. CONCLUSIONS: These data suggest that local upregulation of IL-16 expression contributes to the inflammation observed in seasonal allergic rhinitis. Hypothetically, inhibition of IL-16 expression can be one of several mechanisms by which nasal glucocorticoids achieve their anti-inflammatory effect in allergic rhinitis.
Assuntos
Alérgenos/efeitos adversos , Contagem de Linfócito CD4 , Mucosa Nasal/química , Poaceae/efeitos adversos , Pólen/efeitos adversos , Rinite Alérgica Sazonal/induzido quimicamente , Rinite Alérgica Sazonal/imunologia , Administração Tópica , Adolescente , Adulto , Anti-Inflamatórios/uso terapêutico , Especificidade de Anticorpos/imunologia , Beclometasona/uso terapêutico , Biópsia , Método Duplo-Cego , Exposição Ambiental , Feminino , Glucocorticoides , Humanos , Imunoglobulina E/imunologia , Interleucina-16/análise , Interleucina-16/fisiologia , Masculino , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/patologia , Rinite Alérgica Sazonal/tratamento farmacológico , Sensibilidade e Especificidade , Testes CutâneosRESUMO
We reviewed the biological functions of CD4+ eosinophils, which are observed in peripheral blood, sputum and bronchoalveolar lavage fluid of various diseases. We have shown that CD4 molecules on human eosinophils are induced by tumor necrosis factor-alpha (TNF-alpha) stimulation. Interleukin-16 (IL-16) has been reported to bind a natural soluble ligand for the CD4 molecule. We reported that TNF-alpha-stimulated eosinophils migrate in a time- and dose-dependent manner against IL-16. Theophylline and dexamethasone significantly inhibited CD4 expression. Theophylline inhibited CD4+ eosinophil chemotaxis, but dexamethasone did not. Theophylline may prevent airway inflammation by downregulating the expression of CD4 molecule and CD4+ eosinophil migration. However, dexamethasone may inhibit airway inflammation through the downregulation of CD4 expression.
Assuntos
Antígenos CD4/análise , Quimiotaxia de Leucócito , Eosinófilos/imunologia , Asma/imunologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Dexametasona/farmacologia , Humanos , Interleucina-16/fisiologia , Modelos Imunológicos , Teofilina/farmacologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
Migration of cutaneous dendritic cells is essential for the induction of primary immune responses. Chemotaxis plays an important part in guiding migrating cells through the skin. Therefore, we investigated the influence of interleukin-16, a potent chemoattractant, on the migratory properties of cutaneous dendritic cells. Interleukin-16 added to murine and human skin explant cultures, enhanced emigration of Langerhans cells as well as dermal dendritic cells out of the skin. In contrast to tumor necrosis factor-alpha, intradermally injected interleukin-16 did not reduce the density of Langerhans cells suggesting a chemotactic rather than a mechanistic migration-inducing effect of interleukin-16. In support of these findings, the known migration-promoting effect of tumor necrosis factor-alpha in skin explant cultures could be neutralized by anti-interleukin-16 antibody and vice versa, indicating different but cooperative ways of action for both cytokines. In whole skin explant cultures blocking of the interleukin-16 effect was also achieved with a monoclonal antibody against CD4, the receptor for interleukin-16. In contrast, in cultures of murine epidermis alone no blocking by anti-CD4 became obvious and in CD4-deficient mice Langerhans cell migration in response to interleukin-16 was maintained. This suggests that another receptor for interleukin-16 might be operative for Langerhans cells in the mouse epidermis. Finally, we detected interleukin-16-positive cells in the dermis of skin explants, tumor necrosis factor-alpha-treated and contact allergen-treated skin. Taken together, it seems likely that locally secreted interleukin-16 might serve to enhance the migration of cutaneous dendritic cells and optimize the response to foreign antigen encountering the skin.
Assuntos
Antígenos CD4/fisiologia , Interleucina-16/fisiologia , Células de Langerhans/fisiologia , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Dendríticas/fisiologia , Derme/citologia , Humanos , Injeções Intradérmicas , Interleucina-16/farmacologia , Células de Langerhans/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Técnicas de Cultura de Órgãos , Pele/citologia , Fator de Necrose Tumoral alfa/farmacologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
CCR5 and CXC chemokine receptor 4 (CXCR4) are coreceptors for CD4 as defined by HIV-1 glycoprotein (gp) 120 binding. Pretreatment of T cells with gp120 results in modulation of both CCR5 and CXCR4 responsiveness, which is dependent upon p56(lck) enzymatic activity. The recent findings that pretreatment of T cells with a natural CD4 ligand, IL-16, could alter cellular responsiveness to macrophage-inflammatory protein-1ss (MIP-1ss) stimulation, prompted us to investigate whether IL-16 could also alter CXCR4 signaling. These studies demonstrate that IL-16/CD4 signaling in T lymphocytes also results in loss of stromal derived factor-1alpha (SDF-1alpha)/CXCR4-induced chemotaxis; however, unlike MIP-1ss/CCR5, the effects were not reciprocal. There was no effect on eotaxin/CCR3-induced chemotaxis. Desensitization of CXCR4 by IL-16 required at least 10-15 min pretreatment; no modulation of CXCR4 expression was observed, nor was SDF-1alpha binding altered. Using murine T cell hybridomas transfected to express native or mutated forms of CD4, it was determined that IL-16/CD4 induces a p56(lck)-dependent inhibitory signal for CXCR4, which is independent of its tyrosine catalytic activity. By contrast, IL-16/CD4 desensitization of MIP-1ss/CCR5 responses requires p56(lck) enzymatic activity. IL-16/CD4 inhibition of SDF-1alpha/CXCR4 signals requires the presence of the Src homology 3 domain of p56(lck) and most likely involves activation of phosphatidylinositol-3 kinase. These studies indicate the mechanism of CXCR4 receptor desensitization induced by a natural ligand for CD4, IL-16, is distinct from the inhibitory effects induced by either gp120 or IL-16 on CCR5.
Assuntos
Antígenos CD4/fisiologia , Interleucina-16/fisiologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/metabolismo , Animais , Antígenos CD4/metabolismo , Linhagem Celular , Inibição de Migração Celular , Quimiocina CXCL12 , Quimiocinas CXC/antagonistas & inibidores , Quimiocinas CXC/fisiologia , Quimiotaxia de Leucócito/imunologia , Ativação Enzimática/imunologia , Humanos , Hibridomas , Interleucina-16/genética , Camundongos , Células Estromais/imunologia , Linfócitos T/enzimologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Domínios de Homologia de src/imunologiaRESUMO
IL-16 functions as a chemoattractant factor, inhibitor of HIV replication, and inducer of proinflammatory cytokine production. Previous studies have suggested that CD4 is the receptor for IL-16, because only CD4+ cells respond to IL-16 and both the anti-CD4 Ab OKT4 and soluble CD4 can block IL-16 function. However, these are only indirect evidence of a requirement for CD4, and to date a direct interaction between IL-16 and CD4 has not been shown. In this paper, we report that cells from CD4 knockout mice are as responsive to IL-16 as their CD4 wild-type equivalents in both assays testing for IL-16 function (chemotaxis and production of proinflammatory cytokines). In addition, the inhibitory effect of soluble CD4 on IL-16 function observed using CD4 wild type murine cells was not observed using CD4 knockout cells. These data demonstrate that CD4 is not required for IL-16 function and suggest that another molecule acts as the major receptor.
Assuntos
Antígenos CD4/fisiologia , Citocinas/metabolismo , Interleucina-16/fisiologia , Animais , Antígenos CD4/genética , Células Cultivadas , Quimiotaxia de Leucócito/imunologia , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Leucócitos Mononucleares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The aim of the present study was to characterize the effects of IL-16 and IL-17 on CD4+ and CD8+ T cell responses in patients with acute leukemia and severe chemotherapy-induced leukopenia. We investigated (1) the function of cytokines as growth factors for preactivated monoclonal T cell populations which had been prepared by long-term in vitro culture, and (2) the ability of cytokines to modulate anti-CD3-stimulated proliferation of polyclonal, nonexpanded T cells. A subset of CD4+ and CD8+ clones could utilize IL-16 and IL-17 as growth factors after previous mitogenic activation, but for the CD4+ subset IL-16 responses were significantly higher than IL-17 responses. Cytokine-dependent proliferation was higher for the CD4+ than for the CD8+ clones in the presence of both IL-16 and IL-17. The effects of IL-16/IL-17 were modulated by the presence of exogenous IL-2 and IL-4. The IL-16-responsive CD8+ clones seemed to represent a minor subset expressing the phenotype CD4lowCD8high. The anti-CD3-stimulated polyclonal responses were generally lower for the cytopenic patients than for healthy individuals, and this decreased responsiveness was probably caused by a combination of quantitative T cell defects and suboptimal accessory cell costimulation. Although IL-16 and IL-17 could function as growth factors for a large subset of our T cell clones, both cytokines had either no or only minor effects on the polyclonal T cell responses for cytopenic patients (e.g. only weak enhancement of anti-CD3 and anti-CD3+anti-CD28 responses, no alteration of the cytokine responsiveness profile after anti-CD3 stimulation). We conclude that both IL-16 and IL-17 are potentially immunostimulatory cytokines in patients with acute leukemia and chemotherapy-induced leukopenia, but the final effects of IL-16/IL-17 on proliferative T cell responses are modulated by local immunoregulatory networks.